Immunization with antigen in the presence of agonists for both a Toll Like Receptor (TLR) and CD40 (combined TLR/CD40 immunization) elicits a vigorous expansion of antigen-specific CD8+ T cells that is exponentially greater than the response elicited by either agonist alone. In the process of investigating our originally funded aims directed toward the role of type I IFN (IFN) in TLR/CD40 vaccination, we made the surprising discovery that the T cell response to any adjuvant containing a TLR-agonist is unexpectedly and completely dependent on IL-27. This is in sharp contrast to immunization with infectious vectors such as vaccinia or Listeria monocytogenes (LM) where the impact of IL-27 is negligible. Our data thus reveal a specific, obligate, and previously unappreciated role for IL-27 in non-infectious, subunit vaccine elicited cellular responses. Given the potency with which our combination adjuvant elicits cellular immunity, the obligate role of IL-27 in the cellular response to combined innate/CD40 vaccination is reason enough for further examination. The additional and unexpected reality that essentially all molecularly defined vaccine adjuvants require the participation of IL-27 for eliciting cellular responses only adds to the importance of the studies proposed in this application. To fully understand the role of IL-27 in vaccine-elicited cellular immunity, we will clarify i) the sites and magnitude of IL-27 production, ii) the required pattern f IL-27R expression, iii) the role of IL-27 elicited STAT1 and STAT3 activation in DCs and T cells, and iv) the mechanisms by which vaccination and infectious processes diverge in their degree of IL-27 dependency.